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Hey, "These Sequences May Not Be Junk, After All"! Nature and Heredity Report Function for Non-Coding DNA


The latest issues of the journals Nature and Heredity contain multiple articles reporting function for non-coding DNA. The themes are consistent: types of DNA once thought to be junk now turn out to have function.

A "News & Views" piece in Nature, "Coding in non-coding RNAs," states: "The discovery of peptides encoded by what were thought to be non-coding -- or 'junk' -- regions of precursors to microRNA sequences reveals a new layer of gene regulation. These sequences may not be junk, after all." It then describes a new study just published in Nature which finds that precursors of microRNAs can in fact encode proteins. The news article tells a familiar story: Evolutionary biologist meets new type of DNA. Evolutionary biologist doesn't know what DNA does. Evolutionary biologists assumes DNA is junk and ignores it. Molecular biologist comes along, doesn't think about evolution, and finds out DNA isn't junk and does something important. Here's how the Nature piece puts it:

In the 1970s, as it started to become clear that the genomic regions that encode proteins (the genes) swim in a sea of non-protein- coding sequences, the idea of meaningless, or 'junk', DNA became a hot topic of discussion. Biologists are now well aware of introns, the sequences within genes that separate the coding regions (exons) and which are spliced out at the messenger-RNA level, as well as their notable regulatory roles. However, the term junk DNA has survived and is used loosely to describe genomic sequences between genes, giving them an implied lack of importance.

The debate about the usefulness of non-protein-coding DNA sequences continues to rage. However, within these intergenic regions of a genome are the sequences that produce most plant and many animal pri-miRs. Clearly, these sequences are not useless. Yet the regions of a pri-miR that do not generate the miRNA or the highly structured adjacent sequences have suffered the similar fate of being largely ignored and possibly thought of as junk RNA lacking function.

Essentially, pri-miRs are RNAs from which microRNAs are derived. Researchers have long known that microRNAs can regulate gene expression, but most thought that the pri-miR DNA didn't do anything if it didn't help generate microRNAs. Now it turns out that they are actually a class of DNA that can encode functional proteins, called miPEpS: "Lauressergues and colleagues identified short open reading frames (ORFs) -- sequences that can potentially encode proteins -- in many different pri-miRs of two plant species." Indeed, the proteins generated by pri-miR transcripts also have the ability to promote transcription, ensuring that these proteins stay at certain levels within the cytoplasm. So add a gene-regulation function to these pri-miR sequences. The article concludes:
The experimental discovery of miPEPs and other small peptides such as these raises an inconvenient question: are we missing a vast library of biologically important peptide signals...?
It would seem the answer is yes -- and evolutionary assumptions helped create the problem.

An article in Heredity, "'Satellite DNA transcripts have diverse biological roles in Drosophila'," starts by noting how transposable elements and repetitive DNA were typically thought of as "junk" but are now known to have many types of functions:

It has been known for several decades that a large fraction (>50%) of most eukaryotic genomes corresponds to repetitive DNA sequences, mainly represented by dispersed transposable elements (TEs) and tandemly repeated satellite DNAs (satDNAs). Both classes have been traditionally included into the non-coding fraction of the genome, because they were considered unlikely to encode any protein product useful for the cell. They have been often referred to as 'selfish DNA', 'parasitic DNA' or 'junk DNA', terms usually applied to DNA sequences that spread in the genome by the multiplication of copies that conferred neither advantage nor disadvantage to the fitness of organisms. Their abundance and ubiquitous presence in eukaryotes was traditionally explained by their ability to amplify (intragenomic selection) and as a result of genomic tolerance for such extra and useless genetic material. There is growing evidence showing that TEs may have important functional roles in a genome, participating in gene regulation, chromatin modulation or as functional components of important chromosome structures such as telomeres and centromeres.
The article focuses on the functions of satDNAs, first noting "SatDNAs do not code proteins and have been traditionally viewed as 'monotonous and useless material, able to accumulate until they become a too heavy load for a genome'." Studies found that satDNAs were widely transcribed, but of course advocates of Junk DNA were quick to retort that transcription does not necessarily equal function. Well, the author says, there's good evidence that satDNAs are indeed functional:
I would like to highlight recent and important discoveries concerning the biological utility of transcripts derived from the most abundant and most studied satDNA of Drosophila melanogaster ... [R]epeats from the 1.688 satDNA family are transcribed in embryos and adult flies. They found that 1.688 double-stranded RNAs derived from subfamilies located on chromosomes 2 and 3 are processed into siRNAs (small interfering RNAs) that in turn participate in the heterochromatin formation of both chromosomes. ... 1.688 [satDNA] heterochromatic repeats residing on the X chromosome produce long sense and antisense polyadenylated RNAs comprising approximately four repeats. Depletion of these transcripts in cell culture by RNA knockdown leads to chromosome segregation defects, including the presence of lagging chromosomes in anaphase. ... RNA-immunoprecipitation experiments revealed that 1.688 satRNAs specifically binds to CENP-C, a centromeric protein that together with CENP-A has a key role in kinetochore assembly and function during cell division. SatRNA knockdown led to a significant reduction of CENP-C in the centromeric regions during mitosis. The authors concluded that an interaction between CENP-C and satRNA is required for proper localization of CENP-C (and consequently CENP-A) to centromeres.
The article even notes that "Interactions between satRNAs and centromeric proteins have also been reported in maize and humans" and that "satDNA transcripts contribute for centromeric function in flies, humans and plants." It concludes:
The data above show that satDNA transcripts may be involved in at least three important biological functions as follows: (i) centromere function; (ii) chromatin silencing/ heterochromatin formation and (iii) chromatin modulation and global up regulation of X-linked genes.
Together these kinds of articles highlight a major trend in the research: when we look for function, we find it, and when we don't look for function, someone else finds it.

Image: � WavebreakMediaMicro / Dollar Photo Club.